ABSTRACT. Peripheral nerve injury (PNI) is a common and challenging clinical problem affecting over 3% of U.S. trauma patients. Among combat trauma, the rate of PNI increases to 22%. These patients require extensive resources for initial treatment and therapy, yet they are still left with functional disability. Current treatments for motor, sensory, and mixed PNI include nerve autografts and axonal guidance tubes. However, these methods do not restore complete function in injured patients. Full recovery requires re-innervation of muscle tissue after injury. A major impediment to regeneration is the lack of neurotrophic factor (NTF) release in the injured nerves. The reduction of NTF genes is due to injury-induced overexpression of the Repressor Element-1 Silencing Transcription (REST) factor. In addition, REST represses the expression of a host of neural specific genes required for proper function. To address this challenge, we developed the REST peptidomimetic peptide (RPP), which silences REST activity by inhibiting the specific phosphatase required to maintain its stability, the C- terminal domain small phosphatase 1 (CTDSP1). We demonstrate that RPP increases NTF expression in trauma-induced mesenchymal progenitor cells (TI-MPCs) and that it has great potential to stimulate nerve regeneration in PNI. In this proposal we will optimize the RPP and conduct a comprehensive nonclinical assessment in the following AIMS: AIM 1: OPTIMIZATION OF OUR HIGH AFFINITY CTDSP1 INHIBITOR. AIM 2: ASSESSING THE REGENERATIVE POTENTIAL OF DRUG CANDIDATES. To accomplish these objectives, Alcamena Stem Cell Therapeutics, LLC is collaborating with field leading academic scientists at Johns Hopkins University (JHU), and the Uniformed Services University of the Health Sciences (USHS/DoD). Cumulatively, these studies will inform us on the degree to which our drug candidate improves neuron regeneration, survival and function. Additionally, the use of both human injury induced mesenchymal stem cells and an in vivo rodent model of PNI ensure that our results are translatable towards our long-term goal of addressing the unmet therapeutic needs of PNI patients.